tbuckley/cabot-search huggingface dataset:
LITTIP/Lgr6/HnRNPK complex regulates cementogenesis via Wnt signaling
Authors: Tiancheng Li, Han Wang, Yukun Jiang, Shuo Chen, Danyuan Huang, Zuping Wu, Xing Yin, Chenchen Zhou, Yuyu Li, Shujuan Zou
Journal: International Journal of Oral Science (2023)

Orthodontically induced tooth root resorption (OIRR) is a serious complication during orthodontic treatment. Stimulating cementum repair is the fundamental approach for the treatment of OIRR. Parathyroid hormone (PTH) might be a potential therapeutic agent for OIRR, but its effects still lack direct evidence, and the underlying mechanisms remain unclear. This study aims to explore the potential involvement of long noncoding RNAs (lncRNAs) in mediating the anabolic effects of intermittent PTH and contributing to cementum repair, as identifying lncRNA-disease associations can provide valuable insights for disease diagnosis and treatment. Here, we showed that intermittent PTH regulates cell proliferation and mineralization in immortalized murine cementoblast OCCM-30 via the regulation of the Wnt pathway. In vivo, daily administration of PTH is sufficient to accelerate root regeneration by locally inhibiting Wnt/β-catenin signaling. Through RNA microarray analysis, lncRNA LITTIP (LGR6 intergenic transcript under intermittent PTH) is identified as a key regulator of cementogenesis under intermittent PTH. Chromatin isolation by RNA purification (ChIRP) and RNA immunoprecipitation (RIP) assays revealed that LITTIP binds to mRNA of leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) and heterogeneous nuclear ribonucleoprotein K (HnRNPK) protein. Further co-transfection experiments confirmed that LITTIP plays a structural role in the formation of the LITTIP/Lgr6/HnRNPK complex. Moreover, LITTIP is able to promote the expression of LGR6 via the RNA-binding protein HnRNPK. Collectively, our results indicate that the intermittent PTH administration accelerates root regeneration via inhibiting Wnt pathway. The lncRNA LITTIP is identified to negatively regulate cementogenesis, which activates Wnt/β-catenin signaling via high expression of LGR6 promoted by HnRNPK.
P1388: EFFECTIVENESS AND SAFETY OUTCOMES IN PATIENTS WITH EBV+ PTLD TREATED WITH ALLOGENEIC EBV-SPECIFIC T-CELL IMMUNOTHERAPY (TABELECLEUCEL) UNDER AN EXPANDED ACCESS PROGRAM IN EUROPE
Authors: Sylvain Choquet, Andrew Clark, Cécile Renard, Ben Uttenthal, Sridhar Chaganti, Ralf Ulrich Trappe, Patrizia Comoli, Xinyuan Duan, Baodong Xing, Charley Wu, Laurence Gamelin, Jan-Henrik Terwey, Anke Friedetzky, Daan Dierickx
Journal: HemaSphere (2023)

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Pts with relapsed or refractory (r/r) EBV+ post-transplant lymphoproliferative disease (PTLD) in Europe have had historically poor overall response rates and median overall survival (OS) with no approved treatment options. Tabelecleucel, an off-the-shelf, allogeneic EBV-specific T-cell immunotherapy, has shown clinical benefit and favorable safety profile in the treatment of EBV+ PTLD failing rituximab ± chemotherapy (Prockop EBMT 2021, ATC 2021, ASH 2021, Mahadeo ASH 2022). Its recent European marketing authorization (EMA) represents the first approval of an allogenic T-cell immunotherapy globally. Aims: To report new and updated real-world effectiveness and safety data for r/r EBV+ PTLD pts under an expanded access program (EAP) in Europe. Methods: Atara Bio supported expanded access requests for tabelecleucel in Europe. Here we report on pts who provided consent for research between Sep 2020 and Dec 2022. Results: 74 EAP requests were received from 10 countries for pts with r/r EBV+ diseases. 27 EBV+ PTLD pts consented to secondary use of data and 24 pts had received ≥1 dose of tabelecleucel, including 4 pts with primary central nervous system (PCNS) PTLD. 16 of 24 (66.7%) EBV+ PTLD pts achieved a partial (PR) (33.3%) or complete (CR) (33.3%) response, with median time to response (TTR) of 1.0 (0.8–2.2) mo. Response rate for PCNS PTLD pts was 75% (1 CR, 2 PR). 1-yr OS Kaplan–Meier (KM) estimate rates in EBV+ PTLD were 73.7% (95% CI: 47.3, 88.3) overall, 87.5% in allogeneic hematopoietic stem cell transplant (HCT) and 66.5% in solid organ transplant (SOT), with a median follow-up time of 9.9 (2.4–13.9) and 6.0 (0.7–18.0) mo, respectively. Serious treatment-emergent adverse events (TESAEs) were reported in 7 (29.2%) pts, including 1 fatal event of disease progression. Predefined risks for tabelecleucel were reported in 3 pts; 1 (4.2%) SOT pt had a TESAE of liver transplant rejection (grade 2) and 2 (8.3%) HCT pts had non-serious treatment emergent AEs of chronic graft-versus-host disease (grade 1 and 2). No cases of cytokine release syndrome or tumor flare reaction were reported. No AEs were reported as related to tabelecleucel by the treating physician.Summary/Conclusion: These real-world results for pts with r/r EBV+ PTLD post-HCT or post-SOT, including those with EBV+ PCNS PTLD, treated in the European EAP continue to reinforce the favorable risk:benefit profile of tabelecleucel and are in line with clinical study data supporting its recent EMA approval. Keywords: Immune therapy, Real world data, Epstein barr virus, Post-transplant lymphoproliferative disorder
PB2237: NON-THROMBOTIC INCREASED PORTAL VENOUS PRESSURE IN PATIENTS WITH MYELOPROLIFERATIVE NEOPLASMS: IS IT JUST A HYPOTHESIS?
Authors: Osman Yokus, Veysel Bilgehan Bezirhan, Alper Kimyonok, Istemi Serin
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Thrombotic events in atypical locations, including splenic, mesenteric, hepatic, or portal veins, referred to as “splanchnic vein thrombosis”, are also classically associated with myeloproliferative neoplasms (MPNs). Although portal pressure increase and portal hypertension (pHTN) are associated with the presence of portal thrombus in the course of MPN, intrasinusoidal/intrahepatic obstruction due to extramedullary hematopoiesis is also defined as another factor. Aims: In this study, it was aimed to show the increased portal venous pressure or pHTN without thrombosis in newly diagnosed MPN patients by using the non-invasive method “congestion index”. Methods: The study included patients diagnosed with MPN who applied to Istanbul Training and Research Hospital, Hematology clinic between March-December 2021, had no additional pathology that would cause an increase in portal venous pressure. In addition to the demographic data of the patients at the time of diagnosis such as age, gender, initial laboratory, and cytogenetic results, congestion indexes calculated by the same radiologist by performing doppler ultrasonography with the same doppler ultrasound device were recorded Results: A total of 62 patients, 45 (72.6%) male and 17 (25.4%) female, and 30 healthy volunteers, 19 (63.3%) male and 11 (36.7) female, were included in our study. In the statistical analysis performed by measuring the values between the patient and healthy controls group using doppler ultrasonography, it was determined that there was a significant difference in terms of congestion index results (p=0.026). The mean congestion index was found to be significantly higher in the patient group compared to the healthy controls (0.006±0.02 vs. 0.05±0.01). There was a positive and moderately strong correlation between the congestion index and the portal vein diameter. Summary/Conclusion: The results of the study provide important insights for new studies and emphasize the importance of patient follow-up in terms of non-thrombotic pHTN. Table 1. Statistical analysis performed by measuring the values between the patient and healthy controlsKeywords: Myeloproliferative disorder, Venous thrombosis, Thrombosis
P1597: COMPLEMENT ACTIVATION ON MSCS REGULATE MEGAKARYOPOIESIS BY INTERLEUKIN-35 AND ITS RECEPTOR IL-12RΒ2/GP130 IN IMMUNE THROMBOCYTOPENIA
Authors: Xiaolu Zhu, Qi Chen, Yun He, Chencong Wang, Haixia Fu, Kaiyan Liu, Xiaojun Huang, Xiao-Hui Zhang
Journal: HemaSphere (2023)
P1560: EARLY DIAGNOSIS WITH EBV MONITOR AND PREEMPTIVE RITUXIMAB REDUCES POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER MORTALITY AND INCREASE OVERALL SURVIVAL AFTER ALLOGENEIC TRANSPLANTATION
Authors: Jia-Hau Liu, Ming Yao, Hsin-An Hou
Journal: HemaSphere (2023)

Topic: 30. Infections in hematology (incl. supportive care/therapy) Background: Post-transplant lymphoproliferative disorder (PTLD) is rare complication but with high mortality rate after allogeneic stem cell transplantation (allo-SCT). Clear defining its characteristic and treatment response would be important. Whether serum EBV viral load monitoring could facilitate earlier diagnosis of PTLD and improve its survival is unknown. Aims: We retrospectively analyzed our allo-SCT cohort, and aimed to delineate the PTLD characteristics and to see whether routine EBV serum viral load monitor could improve earlier diagnosis of PTLD and whether the treatment response could be improved with rituximab containing regimen and survival. Methods: Pathology proven PTLD was chart reviewed from our single institute database. Routine EBV DNA PCR monitoring in NTUH since 2007. Prior PTLD cohort (old cohort, n = 12) from Jan 1993 to 2006 in our institute, when routine weekly serum EBV monitoring after allo-SCT was not initiated, was used as the comparator. Overall survival and PTLD related mortality was analyzed using Kaplan–Meier estimation. Results: Between May 2006 and December 2022, 70 cases of PTLD were identified among 1020 patients after allogeneic hematopoietic SCT with an overall incidence of 2.70% at 1 year. At diagnosis, 80% of patients had CMV reactivation, and 62% had grade II aGVHD within 2 months of PTLD diagnosis. HLA-mismatch donors and thymoglobulin use during conditioning regimen were seen in 70% and 100% of patients with PTLD, respectively. Compared with old cohort, with routine EBV monitoring, the extranodal involvement of the PTLD upon diagnosis of the new cohort reduced from 83% to 40% (lung involvement from 67% to 30%), attributable to the early diagnosis of PTLD. By inclusion of rituximab containing regimen, complete response rate increased from 8% in old cohort to 80% in this new cohort. Three-month mortality decreased from 92% to 50% (P <0.02), while PTLD related mortality declined from 64% to 10% (p <0.01). One-year overall survival increased from 8% to 55% (p =.02). Summary/Conclusion: PTLD-related death can be significantly reduced and overall survival could be increased after routine serum EBV DNA monitor after allo-SCT and prompt treatment with rituximab-containing therapy. Keywords: Infection, Allo-SCT, EBV, Post-transplant lymphoproliferative disorder
P1634: HEALTH-RELATED QUALITY OF LIFE IN ADOLESCENT GIRLS WITH HEREDITARY BLEEDING DISORDERS
Authors: Mohamed Elshinawy, Noor Elshinawy
Journal: HemaSphere (2023)

Topic: 33. Bleeding disorders (congenital and acquired) Background: In developing countries, health-related quality of life (HRQOoL) is not very well investigated among adolescent girls with hereditary bleeding disorders (HBDs). After the age of menarche, teenagers with HBD might present with heavy menstrual bleeding (HMB), which poses a significant impact on HRQoL. Aims: The aim of this work is to assess HRQoL in adolescent girls with HBDs and explore its potential predictors. Methods: A cross sectional study done on all girls aged 10-16 years with HBD attending the hematology clinic in our center throughout a duration of 3 months (June - August 2022). 36-Item Short Form Survey (SF-36) was utilized to assess HRQol. Informed consent was taken from patients and their guardians, and ethical approval was obtained from the research committee in our institution. Results: Out of 155 patients recruited, 141 completed the questionnaire. Known cases of von Willebrand disease (VWD) constituted the majority (112/141 = 79.5%). HRQoL score was significantly lower in studied patients, compared to controls (61.1 ± 12.9 vs. 72.4 ± 15.5) (p-value < 0.0001). Multiple regression analysis revealed that the most significant predictor of total HRQoL score was adherence to hormonal therapy (B = 0.59, 95% confidence interval [CI] 0.12 - 1.04, P = 0.008), outweighing other parameters. In addition, proximity to a specialized healthcare center, maintaining a hemoglobin level above 11 g/dL and higher socioeconomic status were significantly correlated with better HRQoL (P-values: 0.02, 0.04 & 0.05 respectively). On the other hand, adherence to tranexamic acid, bleeding phenotype in childhood and family history of bleeding diathesis were not significantly correlated to HRQoL. Summary/Conclusion: Overall, HRQoL is significantly lower in teenager girls with HBD. Factors indicating optimum control of HMB, such as adherence to hormonal therapy, easier access to healthcare & normal Hb for age/gender, together with higher socioeconomic status are significantly correlated with better HRQoL. Recognition of these predictors could help healthcare professionals to develop effective management strategies of HBD in these patients. Establishing a national registry of bleeding disorders is mandatory to deliver better care. Keywords: von Willebrand’s disease
PB1813: REGULATORY MECHANISMS AND THERAPEUTIC POTENTIAL OF THE DLK1-DIO3 LOCUS IN PEDIATRIC ACUTE MEGAKARYOBLASTIC LEUKEMIA
Authors: Lonneke Verboon, Hasan Issa, Dirk Heckl, Jan-Henning Klusmann
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Non-coding RNAs (ncRNAs) are emerging as potential therapeutic targets in pediatric acute megakaryoblastic leukemia (AMKL) due to their cell type and tissue-specific expression patterns. The DLK1-DIO3 locus is highly expressed in megakaryocytes, and AMKL. Knockdown of several members of this locus has been shown to impair megakaryopoiesis. However, the functional role of the DLK1-DIO3 locus in normal hematopoiesis and AMKL remains poorly understood. Aims: In this study, we aimed to investigate the regulatory mechanisms underlying the expression of the DLK1-DIO3 locus in normal megakaryopoiesis and AMKL, and to explore its therapeutic potential in AMKL. Methods: We utilized various techniques to examine the regulatory layers controlling the DLK1-DIO3 locus. CUT&RUN was performed for the key megakaryocytic transcription factor GATA1 and its truncated isoform GATA1s in CMK cells with inducible expression of these factors. We used peak calling to identify GATA1/GATA1s binding regions in the DLK1-DIO3 locus. We also screened GATA1 binding regions and CpG islands of MEG3 for enhancer activity using the dual luciferase assay. To investigate the therapeutic potential of this locus, we used CRISPR/Cas9 to target GATA1/GATA1s binding regions in AML cell lines and analyzed changes in cell proliferation capacity and DLK1/MEG3 expression using FACS analysis and qPCR. Results: We found that GATA1 and GATA1s occupy several genomic locations upstream of DLK1 and MEG3 in CMK cells. We also identified enhancer regions within these GATA1/GATA1s binding regions, with three of these enhancer regions driving strong luciferase expression. In addition, a combination of several CpG islands attributed to MEG3 was required to drive strong luciferase expression. Targeting the GATA1/GATA1s binding regions using CRISPR/Cas9 resulted in decreased proliferation capacity and downregulation of DLK1 and MEG3 expression in AML cell lines. Summary/Conclusion: Our study sheds light on the regulatory mechanisms underlying the DLK1-DIO3 locus in normal megakaryopoiesis and AMKL. We identified GATA1/GATA1s as key regulators of this locus and demonstrated the potential therapeutic benefits of targeting this locus in AMKL. Our findings provide a foundation for further research to explore the clinical application of this locus as a novel therapeutic target in AMKL. Keywords: Acute myeloid leukemia, Pediatric, GATA-1
PB2020: OUTCOMES OF PATIENTS WITH HIGH RISK MYELODYSPLASTIC SYNDROMES
Authors: Imen Ben Amor, Maha Charfi, Moez Mdhaffar, Nour Ben Abdejlil, Faten Kallel, Yosra Fakhfekh, Latifa Khelifa, Rahma Mallek, Imen Frikha, Moez Elloumi
Journal: HemaSphere (2023)

Topic: 10. Myelodysplastic syndromes - Clinical Background: In high-risk myelodysplastic syndromes (MDS), the goal of therapy is to prolong survival and reduce the risk of transformation into acute leukemia, but only a few drugs are currently available for treatment. Aims: We report our therapeutics results of high - risk MDS ‘patients. Methods: This is a retrospective study included patients with high risk MDS classified according to the International Prognostic Scoring System (IPSS) as intermediate-2 or high-risk groups, and treated in Hedi Chaker Hospital in south of Tunisia, between 2015 and 2021. Results: A total of 43 patients were included with a median age of 57 years (24-83), and a sex ratio of 1.1. Five patients (<45 years) underwent an allogeneic hematopoietic stem-cell transplantation (AHSCT), with unfortunately an early toxic death in 3 patients, a relapsed disease in one patient after one year, and one patient is en complete remission after 48 months. Sixteen patients were treated by Azacitidine. 93 cycles were administered with a median duration of therapy of 6 cycles (1-18 cycles). Four patients had achieving a partial response with hematologic improvement, 6 patients had a stable disease and 6 patients had a disease progression. The median of survival of this group was 15 months; overall survival (OS) at 12 and 24 months was 57% and 15 % respectively. Two patients who having a deletion of the long arm of chromosome 5 received Lenalidomide allowing to obtain in a transfusion independence in both patients, with a transient cytogenetic response and after that a progression to acute leukemia in 24 months in one patient, and persistent hematologic response after 48 months of follow up in the other patient. The remains of patients (20 patients) received best supportive care with an (OS) of 24% at 12 months and 9% at 24 months. The overall survival (OS) of the whole cohort was respectively 42% and 13% at 12 and 24 months. Summary/Conclusion: AHSCT remains the only curative treatment when, but this concerns a minority of patients. Azacitidine improve the survival of patients compared to those received supportive care. The current challenge in the management of higher risk MDS is to improve outcome by combining classical hypomethylating agents with novel drugs. Keywords: MDS
P1618: REAL-WORLD DATA ON EMICIZUMAB: CORRELATION BETWEEN DRUG PLASMA LEVELS, GLOBAL PROCOAGULANT STATUS AND SPONTANEOUS JOINT ANNUALIZED BLEEDING RATE
Authors: Francisco José López Jaime, Ana Marco-Rico, Adrián Montaño, Francisco Daniel Muñoz López, Ángeles Palomo-Bravo, Pascual Marco, Ihosvany Fernández Bello
Journal: HemaSphere (2023)

Topic: 33. Bleeding disorders (congenital and acquired) Background: Emicizumab has improved the management of patients with hemophilia A with or without inhibitors. However, real-world data on drug plasma levels and their correlation with thrombin generation, viscoelastic clotting capacity and spontaneous joint annualized bleeding rate (SJABR) are scarce. Aims: Correlation between emicizumab plasma levels, ex-vivo procoagulant profile and SJABR in a cohort of patients on emicizumab prophylaxis were evaluated. Methods: In a multicenter study, whole blood from subjects on emicizumab prophylaxis was drawn after reaching plasma drug steady state. Emicizumab plasma levels was centrally evaluated by an aPTT modified test (Stago). Number of spontaneous joint bleedings (SJB) were retrospectively recorded from the patients’ clinical history. Ex-vivo procoagulant profile was evaluated by thrombin generation test (TGT, Genesia®, Stago®) and rotational thromboelastometry (ROTEM®, naTEM® test, Werfen®). Results: Nineteen patients with a median (25th-75th percentiles) [minimum-maximum] age of 15.2 (6.7-28.5) [2.2-47.9] years old were analysed. Plasma levels of emicizumab was 44.0 (38.0-51.0) [27.2-69.2] mcg/mL. Throughout a follow-up period of 46.0 (26.0-78.9) [3-225] weeks, none of the patients presented SJB. No correlation between emicizumab plasma levels and TGT or ROTEM® were detected. Patients presented lower values of both thrombin generation peak (Peak) and endogenous thrombin potential (ETP) compared to controls, though, by the contrary, ROTEM® showed similar (e.g., CT and CT+CFT) or even higher procoagulant profile (e.g., lower values of CFT in patients) compared to healthy subjects (Table 1). Summary/Conclusion: Emicizumab provided excellent protection of patients from SJB along the observational period. Plasma levels of emicizumab may be quite variable between patients but this fact does not impact negatively on the development of SJB. Ex-vivo global procoagulant profile of subjects do not correlate with emicizumab plasma levels. TGT and ROTEM® showed contradictory results describing lower thrombin generation potential compared to healthy controls in TGT but similar or even higher procoagulant function in patients by ROTEM®. Further studies are needed to explain these findings and their clinical significance. Table 1: Global assay results. TGT (Genesia®) expressed as % of healthy controls (assumed as 100%). Values of ROTEM® parameters are included also for comparison.Keywords: Hemophilia A, Thrombin generation, Thrombelastograph
PB2253: HYPEREOSINOPHILIC SYNDROMES: CARDIAC EMERGENCY IN THE ELDERLY
Authors: Ahlam Gougas, Maamar Mouna, Hajar Khibri, Wafaa Ammouri, Hicham Harmouche, Zoubida Tazi Mezalek, Mohammed Adnaoui
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Hyper-eosinophilia syndromes (HES) are defined as chronical (> 6 months) blood eosinophilia (HE) ≥ 1500/mm3 and/or tissue eosinophilia (HE) associated with tissue damage relative to eosinophil toxicity. It is a heterogeneous entity that includes clonal (neoplastic) HES, reactive HES, and unexplained HES. The peak frequency of HES is between 30 and 50 years of age, but it may also occur in the elderly. Eosinophilic myocarditis constitutes 40% of HES. It is considered as an “eosinophilic emergency” in diagnosis and treatment. Aims: Show the severity of eosinophilic myocarditis in the elderly and the necessity of an early diagnosis and treatment. Methods: A case report of a patient hospitalized at the geriatric unit of department of haematology Results: A 79-year-old patient with cardiovascular risk factors including blood hypertension on amlodipine, type 2 diabetes on insulin, and dyslipidaemia. She had a drug toxidermy type DRESS syndrome after taking steroidal anti-inflammatory drugs for chronic gonalgia; hypereosinophilia was objectified at 9313/ mm3. The patient received symptomatic IV methylprednisone therapy with oral prednisone relay; all medicinal products were discontinued with positive clinical outcome and liver cytolysis regression. Initial cardiac examination did not show an aspect of myocarditis. The progression was marked by the persistence of major blood eosinophilia (5600/ mm3), despite oral corticosteroid therapy. An etiological investigation was in favour of idiopathic HES. Two months later, the patient developed diffuse acute abdominal pain. The electrocardiogram (ECG) showed an ST elevation a Q-wave of necrosis. Coronary angiography showed no abnormalities. Transthoracic Ultrasound (TT) revealed global hypokinesia, a 25% ejection fraction (EF), with an appearance reminiscent of eosinophilic myocarditis. The patient died 12 hours later, following a sudden cardiac arrest despite cardiopulmonary resuscitation. Summary/Conclusion: Eosinophilic myocarditis is a potentially fatal emergency. Hence the importance of an early diagnosis and treatment; especially in the geriatric population characterized by semiological clinical atypia and polypathology Keywords: Hypereosinophilic syndrome, Elderly